Open AccessCardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptor γ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension
Author(s) -
Kusunoki Hiroshi,
Taniyama Yoshiaki,
Rakugi Hiromi,
Morishita Ryuichi
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000103
Subject(s) - irbesartan , medicine , blockade , angiotensin ii , endocrinology , angiotensin ii receptor type 1 , receptor , peroxisome proliferator activated receptor , pharmacology , angiotensin receptor , blood pressure
Background “Aldosterone breakthrough” observed in patients receiving long‐term treatment with angiotensin blockade is strongly associated with increased risk of left ventricular hypertrophy, poor exercise capacity, refractory proteinuria, and declining glomerular filtration rate through the profibrotic actions of aldosterone. To overcome aldosterone breakthrough, we examined the additional organ‐protective actions of irbesartan, because irbesartan is an angiotensin II type 1 receptor (AT1R) blocker (ARB) with peroxisome proliferator‐activated receptor ( PPAR )γ agonistic effects, which mediate organ‐protective effects independent of AT1R blockade. In this study, we examined the organ‐protective effects of irbesartan in a salt‐sensitive hypertension model using AT 1aR knockout mice. Methods and Results Aldosterone and 1% NaCl treatment resulted in a significant increase in severe cardiac and renal fibrosis. Irbesartan, but not losartan, significantly reduced renal fibrosis, glomerular injury through inhibition of macrophage infiltration, epithelial–mesenchymal transition, and oxidative stress. Similarly, cardiac fibrosis and myocyte hypertrophy were decreased by irbesartan, but not losartan, treatment, associated with a significant reduction in oxidative stress. Importantly, anti–hepatocyte growth factor (HGF) neutralizing antibody and a PPAR γ antagonist ( GW 9662) attenuated these organ‐protective effects of irbesartan. HGF protein level was increased by irbesartan, especially in the kidney and heart, while GW 9662 treatment inhibited the increase in HGF level. Conclusions In this study, we showed that irbesartan, which has not only AT 1aR‐blocking effects, but also PPAR γ agonistic effects accompanied by HGF expression, inhibited organ damage by aldosterone and salt treatment. Second‐generation ARB s such as irbesartan, which has the dual actions of AT 1R blockade and PPAR γ activation, may have clinical value for the treatment of hypertensive patients with aldosterone breakthrough.